Arrowhead Completes Dosing Healthy Volunteers and Initiates Transition to Patients in Phase 1 Study of ARC-AAT

PASADENA, Calif.–(BUSINESS WIRE)–

Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical

company developing targeted RNAi therapeutics, today announced that it

completed dosing healthy volunteers and will begin dosing patients in an

on-going phase 1 study of ARC-AAT, the Company’s clinical candidate for

the treatment of liver disease associated with Alpha-1 Antitrypsin

Deficiency (AATD). AATD is a rare genetic disorder that can severely

damage the liver and lungs of affected individuals. The study was

designed to begin dose escalation in healthy volunteers (Part A) and

transition into patients (Part B) when a predefined knockdown target is

achieved. That target is at least 30% reduction of serum AAT levels in 3

subjects or greater than 60% reduction in a single subject. This was met

during the third cohort. All three dose levels tested appear to be

generally well tolerated and the data safety committee has cleared the

study to move into patients with AATD. Dosing in patients may now begin

at the highest dose level used in Part A and then continued dose

escalation may proceed under the protocol. The company expects to

complete the Phase 1 study by the end of 2015.

“We are excited that Part A of the phase 1 study is complete and that we

can now begin studying ARC-AAT directly in patients with PiZZ genotype

AATD,” said Bruce D. Given, M.D., Arrowhead’s Chief Operating Officer.

“The lung disease associated with AATD is frequently treated with AAT

augmentation therapy. However, there is a great need in the field to

identify new treatment options for the AATD-related liver disease.

Currently, the only option for severe cases is liver transplant, with

all of its attendant risks and availability issues. We think ARC-AAT is

a very promising program that may potentially provide a better option

for patients and physicians.”

ARC-AAT is comprised of novel unlocked nucleobase analog containing RNAi

trigger molecules (UNA) that are co-administered with Dynamic

Polyconjugates (DPCs) to enable the escape of the UNA from endosomes.

The ratio of UNA to DPC is 2:1 by weight. In Part A of the study, three

cohorts of six participants each received ARC-AAT at doses of 0.38

mg/kg, 1.0 mg/kg, and 2.0 mg/kg of UNA, and 0.19 mg/kg, 0.5 mg/kg, and

1.0 mg/kg of DPC, respectively.

The Phase 1 trial is a multi-center, randomized, placebo-controlled,

double-blind, single dose-escalation first-in-human study to evaluate

the safety, tolerability and pharmacokinetics of ARC-AAT and the effect

on circulating AAT levels. The study has been enrolling in dose cohorts

of six participants each, with participants randomized at a ratio of 2:1

(active:placebo) to receive a single intravenous injection of either

ARC-AAT or placebo (normal saline). The study consists of two parts;

Part A in healthy volunteers, which has been completed, and Part B to be

conducted in patients with PiZZ genotype AATD. The study evaluates

participants for 28 days following dosing, with additional follow-up if

needed every 2 weeks until AAT levels return to baseline.

“The Alpha-1 Foundation and the entire Alpha-1 community are excited to

see this program move forward,” said John Walsh, president and chief

executive officer of the Alpha-1 Foundation. “We and The Alpha-1

Project, the Foundation’s venture philanthropy arm, will continue to

work closely with Arrowhead on clinical trial recruitment and provide

additional assistance to get this potentially life saving therapy to

adults and children with liver disease due to Alpha-1.”

About Alpha-1 Antitrypsin Deficiency (AATD)

AATD is an autosomal recessive genetic disorder associated with liver

disease in children and adults and pulmonary disease in adults. Alpha-1

antitrypsin is a circulating glycoprotein protease inhibitor of the

serpin family encoded by the AAT gene and primarily synthesized in the

liver. The physiologic function is inhibition of neutrophil proteases to

protect healthy tissues during inflammation and prevent tissue damage.

The Z mutant is the most common disease variant and has a single amino

acid substitution that results in improper protein folding causing

severe impairment of secretion from hepatocytes. This lack of secretion

leads to accumulation of mutant Z-AAT polymers, which form globules in

the hepatocyte endoplasmic reticulum. This triggers continuous

hepatocyte injury, leading to fibrosis, cirrhosis, and increased risk of

hepatocellular carcinoma.

In clinical practice, approximately 96-98% of AATD-related disease is

due to the homozygous PiZZ genotype. PiZZ individuals have severe

deficiency of functional AAT leading to pulmonary disease and hepatocyte

injury and liver disease. Lung disease is frequently treated with AAT

augmentation therapy. However, augmentation therapy does nothing to

treat liver disease, and there is no specific therapy for hepatic

manifestations. There is a significant unmet need as liver transplant is

currently the only available treatment for severe liver manifestations.

The mean estimated prevalence of AATD in the U.S is 1 per 3000-5000, or

approximately 100,000 patients. AATD is also an important cause of

pediatric liver disease with an estimated prevalence in children of

approximately 20,000 patients, and 50-80% likely to manifest liver

disease during childhood. It is an orphan disease that appears to be

frequently misdiagnosed or undiagnosed. European prevalence is estimated

to be 1 per 2500.

About ARC-AAT

Arrowhead’s ARC-AAT is being investigated for the treatment of liver

disease associated with Alpha-1 Antitrypsin Deficiency (AATD), a rare

genetic disease that severely damages the liver and lungs of affected

individuals. ARC-AAT employs a novel unlocked nucleobase analog (UNA)

containing RNAi trigger molecule designed for systemic delivery using

the Dynamic Polyconjugate delivery system. ARC-AAT is highly effective

at knocking down the Alpha-1 antitrypsin (AAT) gene transcript and

reducing the hepatic production of the mutant AAT (Z-AAT) protein.

Reduction of liver production of the inflammatory Z-AAT protein, which

is likely a cause of progressive liver disease in AATD patients, is

important as it is expected to halt the progression of liver disease and

potentially allow fibrotic tissue repair. The Company is conducting a

single dose Phase 1 clinical study, with part A in healthy volunteers

and part B in AATD patients.

About Arrowhead Research Corporation

Arrowhead Research Corporation is a biopharmaceutical company developing

targeted RNAi therapeutics. The company is leveraging its proprietary

Dynamic Polyconjugate™ delivery platform to develop targeted drugs based

on the RNA interference mechanism that efficiently silences

disease-causing genes. Arrowhead’s pipeline includes ARC-520 for chronic

hepatitis B virus and ARC-AAT for liver disease associated with Alpha-1

antitrypsin deficiency.

For more information please visit http://www.arrowheadresearch.com,

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Litigation Reform Act of 1995. These statements are based upon our

current expectations and speak only as of the date hereof. Our actual

results may differ materially and adversely from those expressed in any

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Research Corporation’s most recent Annual Report on Form 10-K and

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Source: Arrowhead Research Corporation

Arrowhead Research Corporation
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ir@arrowres.com
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